Project Summary Progressive pancreatic cancer (PDA) is a lethal disease. The highly invasive and metastatic nature of PDA cells renders the tumor incurable. The molecular changes leading to this invasive behavior remain poorly understood. While certain genetic and epigenetic alterations have been well known for years, to date this has not resulted in useful preventive and/or therapeutic modalities. Our long-term research goal is to identify driving alterations in gene expression that can be utilized to develop effective strategies to detect and treat PDA. The studies outlined in this proposal will directly determine the role of epigenetics in PDA progression by dissecting the functions of KDM4C, a histone demethylase, thus uncovering the causative mechanisms underlying the acquisition of PDA invasive phenotype, a hallmark of PDA progression. It is well established that Wnt/?-catenin signaling is critical for cancer cell proliferation, invasion and cancer progression, whereas little is known about the epigenetic mechanisms for the activation of those tumor-promoting genes downstream of Wnt/?-catenin signaling. We found for the first time that KDM4C is drastically increased in invasive PDA and this dysregulation critically promotes PDA biology, whereas PanINs do not exhibit substantially elevated KDM4C expression. Concurrently, our recent study also has shown a consistent increased expression of genes downstream of Wnt/?-catenin signaling in invasive PDA as compared to that in PanINs. Causally linking KDM4C to overactivation of Wnt/?-catenin signaling and functionally interrogating the underlying mechanisms are fundamentally important in understanding PDA progression and designing effective intervention strategies. We postulate that upregulation of KDM4C expression and function causes overactivation of Wnt/?-catenin signaling and consequential acquisition of malignant phenotype in PDA, i.e., a switch from premalignant PanINs to invasive PDA. To test our hypothesis, we propose three specific aims: 1) to investigate the role and mechanisms of KDM4C in enhancing Wnt/?-catenin transcriptional function and uncover a novel mechanism for the persistent activation of ?-catenin-mediated transcription in PDA (Aim 1); 2) to evaluate the function of KDM4C expression on PDA biology (Aim 2); and 3) to investigate the molecular mechanisms underlying the dysregulated KDM4C expression and its clinical relevance and significance in PDA progression (Aim 3). If the studies of those specific aims are completed, not only will we uncover new molecular mechanisms for the activation of Wnt/?-catenin signaling pathways during PDA progression, but also for first time will we reveal the biological and clinical impacts of the epigenetic regulation in general and KDM4C in particular on PDA progression; and help identify potential targets for developing novel intervention strategies.